Drugs for the symptomatic relief of common cold symptoms have been widely used for decades. Common cold is a self-limited illness, typically of short duration with usually mild symptoms normally lasting for a few days up to about two weeks in severe cases. The symptoms of a common cold include sneezing, rhinorrhea (runny nose), nasal congestion, sore or scratchy throat, cough, hoarseness, and mild general symptoms like headache, chilliness, and general malaise.
More than 200 different viruses are known to cause the symptoms of the common cold. Among these, the rhinoviruses account for more than 30% of colds in adults. Other common cold inducing viruses include the Corona viruses, the Influenza viruses, A, B and C. Infections by viruses may be associated with otitis media, sinusitis, exacerbation of asthma and chronic lung disease, and, in infants, serious lower respiratory tract disease.
Currently, however, no antiviral drug is available for the treatment of common cold. Therefore, treatment is based on the managing of symptoms associated with the common cold.
A number of medicaments have been developed for the treatment of symptoms associated with common cold through stimulation of the adrenergic receptors in the sympathetic nervous system of the nose or through competitive inhibition of cholinergic receptors.
Topical sympathomimetic decongestants such as imidazoline alpha-adrenergic agonist (a vasoconstrictor), e.g. xylometazoline, have been administered as either nasal spray or nose-drops in order to relieve nasal congestion and prevent sinusitis. A widely used medicament on the market comprising xylometazoline is the nasal spray, Zymelin®. Other topical nasal decongestants include Phenylephrine, Oxymetazoline, Naphazoline, Tetrahydrozyline, Ephedrine, Etaphedrine, Clonazoline, Dimepropion, Fenoxazoline and Indanazoline.
Agents with local anticholinergic activity in the upper respiratory tract, such as ipratropium, a derivative of N-isopropyl noratropine, are also useful for treating symptoms of common cold. ipratropium bromide is today used as an agent efficacious in normalising nasal secretion in patients with rhinorrhea associated with perennial rhinitis and in reducing nasal secretion in patients suffering from common cold. Ipratropium bromide is available on the market as a nasal spray, Atrovent®, for the symptomatic treatment of rhinorrhea associated with perennial rhinitis. Other topical nasal anticholinergic agents include oxitropium bromide, anisotropine methylbromide, clidinium bromide, glycopyrrolate and mepenzolate bromide.
Following intranasal administration of xylometazoline hydrochloride, the vasoconstrictor effect generally occurs within five to ten minutes and the effect may last for 5-6 hours and up to 12 hours. Likewise, the maximal effect following administration of ipratropium bromide is reached after 0.5 to 1.5 hrs with a mean duration of 6 hours.
Ipratropium bromide is further reported to irritate the nasal mucosa by desiccating the nasal mucosa, thereby causing discomfort to the user of medicaments comprising ipratropium bromide.
The combination of xylometazoline and ipratropium or suitable derivatives or salts thereof into one medicament for nasal administration will involve that more than one symptom can be treated simultaneously, thereby further reducing the degree to which the patient is affected by the common cold. Furthermore, the number of doses and/or the daily dose needed for achieving the relieving effect on common cold may be reduced.
However, no such medicament exists today. Both agents, ipratropium or salts thereof and xylometazoline or salts thereof, have each been reported in the literature to have poor stability in aqueous solutions. Literature data show that aqueous solutions of xylometazoline hydrochloride and ipratropium bromide have stability optima at pH 2 and pH 3.5, respectively (Grabowska I et al. Acta, Polon Pharm XLI, 359-363, 1984 and Bell G et al. Pharm Res 7: Suppl S129, 1990). Xylometazoline hydrochloride is fairly stable in acidic media, whereas in neutral and alkaline media, the rate of degradation is considerably increased. Ipratropium bromide is an ester and undergoes hydrolysis in aqueous solution to give tropic acid and an alcohol. The hydrolysis increases with increasing/decreasing pH values above pH 3.5 and below pH 3.5. With the aim of providing a medicament comprising the two active agents, the pH should be advantageous for nasal application. Therefore, a medicament for nasal application should not have a pH in the order of the stability optima reported for ipratropium bromide and xylometazoline hydrochloride, respectively, but rather a pH about pH 6 to pH 7. Unfortunately, in this pH range the two agents are subject to degradation.
Formulations comprising ipratropium bromide already exist, e.g. formulated as an aerosol, either containing up to 5% of ipratropium bromide (by weight) or in non aqueous suspensions (U.S. Pat. No. 5,955,058 and WO 99/65464).
Furthermore, the combination of drugs with different pharmacological activity in the treatment or prevention of nasal diseases have been disclosed in the form of a nasal spray (WO94/05330). Preferably, such drugs are anti-inflammatory agents, antihistaminic agents, anticholinergic agents, anti-allergic agents or vasoconstrictors. Furthermore, WO98/48839 discloses topically applicable nasal compositions comprising a topical anti-inflammatory agent combined with at least one agent suitable for topical nasal administration and selected from the group consisting of a vasoconstrictor, a neuraminidase inhibitor, a leukotriene inhibitor, an antihistamine, an anti-allergic agent, an anticholinergic agent, an anaesthetic and a mucolytic agent. The compositions may be administered as nasal sprays or as nose drops for the treatment of nasal and sinus conditions. In WO 93/09764, the combination of anti-viral and anti-inflammatory agents is disclosed for the treatment of common cold and related disorders. In one embodiment thereof, the combination include ipratropium and xylometazoline dissolved or suspended in a liquid propellant.
Co-administration of ipratropium and xylometazoline has been investigated by Borum et al. In a trial by Borum et al, each nostril was primed with xylometazoline five minutes prior to ipratropium administration in order to secure adequate distribution of ipratropium to the nasal epithelium (Borum P et al, Am Rev Res Dis, 123, 418-420, (1981) and Borum P et al, European Journal of Respiratory Diseases, 64, Suppl 128I, 65-71, (1983).